Projects

UCP3 Insufficiency Contributes to Heart Failure in Diabetes

Patients with insulin resistance and type 2 diabetes have poor cardiac outcomes following myocardial infarction (MI) and are at increased risk of developing heart failure with preserved ejection fraction (HFpEF). In both cases, an increase in myocardial oxidative stress has been linked to this poor prognosis. In his previous studies, Dr. Harmancey found that chronic hyperinsulinemia induces a state of selective insulin resistance that is directly responsible for the down regulation of the mitochondrial uncoupling protein 3 (UCP3) in the heart (PMID 26555260). Because increased UCP3 activity has been linked to decreased oxidative stress in cells, a major focus of our lab has been to determine whether the partial loss of UCP3 may contribute to heart failure progression in the diabetic heart.

Using a novel rat model of UCP3 haploinsufficiency (ucp3^+/-), we demonstrated that partial loss of cardiac UCP3 is sufficient to increase mitochondrial reactive oxygen species (ROS) generation at reperfusion, thereby promoting mitochondrial dysfunction and a decreased capacity for the heart to rely on long-chain fatty acid (LCFA) oxidation for maintenance of contractile function. Furthermore, preliminary findings in the isolated working rat heart suggest that supplying the UCP3 insufficient heart with medium-chain fatty acids (MCFA) as an alternate source of fuel decreases mitochondrial ROS generation and improves contractile recovery at reperfusion following ischemia (PMID 30374710). Using the same animal model, our group provided further evidence that UCP3 insufficiency also exacerbates key pathological features of left ventricular diastolic dysfunction during hypertension, including an increase in LV filling pressures, increased cardiac inflammation, increased extracellular matrix deposition and increased left ventricular wall thickness (PMID 34533037).

Those findings highlight the importance of UCP3 in maintaining the oxidative stress balance and energy homeostasis in the heart. They also confirmed that UCP3 insufficiency is responsible for the poor post-ischemic recovery of the heart and for a greater risk for developing HFpEF in diabetes. Our team is currently testing intravenous infusion of MCFA-based lipid emulsions as a potential metabolic intervention to improve cardiac recovery of type 2 diabetic patients at reperfusion following myocardial infarction.

 

Targeting NR4A2 for Regeneration of the Failing Heart

By integrating the neurohumoral and biomechanical stimuli relayed through various intracellular signal-transduction pathways, transcription factors coordinate metabolic, structural and functional adaptation of the heart to environmental changes. The Nuclear Receptor Subfamily 4 Group A (NR4A) receptors are ligand-independent transcription factors acting as immediate/early response genes induced by a variety of environmental cues. Although cardiac expression of the NR4A receptors increases in several rodent models of pressure overload and under beta-adrenergic receptor stimulation, we know very little about their role in the regulation of cardiac physiology.

Our lab previously demonstrated that NR4A2 acts as a negative feedback regulator of the beta-adrenergic receptor-mediated growth response in isolated adult rat ventricular myocytes (PMID 31188636). Moreover, we found that NR4A2 expression is induced by glucose and insulin in the heart, suggesting that the activity of this factor could be altered during obesity and diabetes (PMID 27940566). In order to gain further insight into the effects of cardiac NR4A2 in vivo, the team has generated mice to mediate tamoxifen inducible, cardiac-specific overexpression of the nuclear receptor (Nr4a2-icTg mice). Investigations with this new model revealed that cardiac NR4A2 overexpression accelerates the transition from compensated to decompensated hypertrophy in hearts from male and female adult mice subjected to pressure overload by constriction of the aorta. Unbiased analyses of the cardiac transcriptome and proteome further indicated that sustained NR4A2 activity inhibits oxidative phosphorylation and mitochondrial biogenesis to favor glycolysis, which reactivates cell cycle progression and DNA synthesis in adult cardiac myocytes (PMID 35776225). Based on these findings, our team is currently investigating the potential role of NR4A2 as a novel regulator of cardiomyocytes proliferation, and how the activity of this factor could be modulated in a beneficial way to improve regeneration of the failing heart.

 

Role of Ectopic Olfactory Receptors in Heart Failure

G protein-coupled receptors (GPCRs) are critical regulators of cardiac physiology and a key therapeutic target for the treatment of heart disease. Ectopic olfactory receptors (ORs) are GPCRs expressed in extra-nasal tissues which have recently emerged as new mediators in the metabolic control of cardiac function. The full extent of cardiac OR genes expression and their potential involvement in disease mechanisms remain unclear.

In our most recent study, we set out to profile OR gene expression in the human heart, to identify ORs whose expression is modified by heart failure, and to provide evidence suggestive of a role for those altered ORs in the pathogenesis of heart failure. Left ventricular tissue from patients diagnosed with ischemic heart failure and non-failing heart samples were subjected to a two-step transcriptome analysis consisting in the quantification of 372 distinct OR transcripts with a custom real-time PCR array and the simultaneous determination of the global cardiac gene expression signature of each individual by RNA sequencing. This strategy led to the identification of >160 ORs expressed at significant levels in the human heart, with at least 38 of those receptors differentially regulated with heart failure. Co-expression analyses predicted the involvement of dysregulated ORs in the alteration of biological processes such as mitochondrial function, extracellular matrix remodeling, and inflammation. We plan to provide this data set as a resource for investigating roles of ORs in the human heart, with the hope that it will assist in the identification of new therapeutic targets for the treatment of heart failure.